Blend containing carbamate compound for prevention, mitigation, or treatment of schizophrenia

ABSTRACT

The present invention relates to a blend for prevention, mitigation, or treatment of schizophrenia, the blend containing a carbamate compound of chemical formula 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof and, more specifically, to a blend and a pharmaceutical composition each containing a carbamate compound of chemical formula 1 and aripiprazole, and to a use thereof for treating schizophrenia.

FIELD

The present invention relates to a combination comprising a carbamatecompound of the following Formula 1, or a pharmaceutically acceptablesalt, solvate or hydrate thereof for preventing, alleviating or treatingschizophrenia, more specifically to a combination comprising thecarbamate compounds of Formula 1 and aripiprazole:

wherein,

R₁, R₂, A₁ and A₂ are as defined herein.

BACKGROUND

Schizophrenia, a representative psychiatric disorder, is a syndrome ofvarious psychotic symptoms in which the main pathology is a thoughtdisorder and complex symptoms appear in various areas such as speech,behavior, emotion and cognition that are associated with or derived fromsuch thought disorder. It is a series of symptoms that have long beencalled madness in human history.

In general, the prevalence of schizophrenia is approximately 1% of theworld's population and has been observed to be constant regardless ofpopulation characteristics, and regional and cultural differences, suchas Western and Eastern, and developed countries and developingcountries. Although the cause of schizophrenia is not clear, itslikelihood of development is said to increase due to geneticpredisposition or environmental factors such as problems duringpregnancy, parenting environment and stress.

Symptoms of schizophrenia can be classified into a positive symptom, anegative symptom, a cognitive symptom and a residual symptom. Positivesymptoms refer to abnormal and bizarre symptoms that appear externally,psychotic symptoms that cannot be found in healthy people, includingabnormalities in sense such as auditory hallucinations or visualhallucinations; abnormalities in thoughts such as unrealistic andbizarre delusions; and disorders in the thinking process in which anabnormality occurs in the flow of thought. Negative symptoms refer to aphenomenon in which a normal emotional reaction or behavior decreases tobecome a dull state and which show poverty of the content of thought,decrease in motivation, social withdrawal, etc. Negative symptomsgenerally do not respond better to medication than positive symptoms.Cognitive symptoms refer to symptoms showing difficulty in maintainingconcentration and a decrease in the ability to learn new information ororganize one's thoughts. These symptoms make patients unable to do whatthey used to do well in the past, and significantly reduce memory andproblem-solving ability, thereby degrading the patients' social andoccupational functions, causing the patients to fail to return tosociety and to become unemployed and to experience frustration.Cognitive symptoms refer to symptoms showing difficulty in maintainingconcentration and a decrease in the ability to learn new information ororganize one's thoughts. Patients are not able to do what they used todo well in the past, and show a significant reduction in memory andproblem-solving ability. Cognitive symptoms are less noticeable, butdecrease the social and occupational functions of schizophreniapatients, causing them to fail to return to society and to experiencefrustration.

Schizophrenia can be presented in various forms depending on thesymptoms and signs as described above. Schizophrenia includes not onlyparanoid schizophrenia, disorganized schizophrenia, catatonicschizophrenia and undifferentiated schizophrenia, but alsopost-schizophrenic depression, residual schizophrenia, simpleschizophrenia and unspecified schizophrenia. In addition thereto,schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to another medical condition, substance/medication-inducedpsychotic disorder, or psychotic disorder of unknown cause are includedin schizophrenia in a broad sense.

Typical antipsychotic drugs such as haloperidol and chlorpromazine, andatypical antipsychotic drugs such as aripiprazole, risperidone andclozapine have been developed, and these drugs are known to be effectiveespecially for the positive symptoms of schizophrenia. When patientsstart medication, psychomotor agitation, hallucinations, etc. of theacute phase generally improve within a few days, and delusions alsoimprove within a few weeks. It is known that in most patients, asignificant portion of the acute phase symptoms improves when theappropriate medication is maintained at the appropriate dose for 6-8weeks. However, when patients first take antipsychotic drugs, many ofthem experience drowsiness and dizziness, and they often experienceblurred vision, palpitations, menstrual changes and skin rashes.

Conventional antipsychotic drugs alleviate or relieve the symptoms ofpatients to improve the quality of life, but this does not inducecomplete healing and their use is limited due to side effects. Hence,these drugs have limited therapeutic value in the management ofschizophrenia, and there is a need to develop new drugs with improveddrug efficacy and side effects. In particular, no drug is presentlysatisfactory to treat the negative or cognitive symptoms ofschizophrenia, and thus development of such a drug is necessary.

SUMMARY Problem to be Solved

The present invention is intended to provide a combination and apharmaceutical composition that exhibits an improved effect in theprevention, alleviation or treatment of schizophrenia without increasingside effects.

Technical Solution To The Problem

The present inventors have thought that combining the conventional(existing) antipsychotic agents such as aripiprazole with drugs havingdifferent mechanisms of action could maintain or elevate their efficacywhile reducing side effects by decreasing the dose required for theefficacy of the conventional antipsychotic agents, and thus haveconducted a thorough study.

As a result, the present inventors have selected a carbamate compound ofthe following Formula 1, or a pharmaceutically acceptable salt, solvateor hydrate thereof, as a drug having a mechanism of action differentfrom that of the conventional antipsychotic agents:

wherein,

R₁ and R₂ are each independently selected from the group consisting ofhydrogen, halogen, C₁-C₈ alkyl, halo-C₁-C₈ alkyl, C₁-C₈ thioalkoxy andC₁-C₈ alkoxy; and

one of A₁ and A₂ is CH, and the other is N.

In addition, as the conventional antipsychotic agent, the presentinventors have selected an atypical antipsychotic agent from the groupconsisting of aripiprazole, asenapine, clozapine, iloperidone,olanzapine, lurasidone, paliperidone, quetiapine, risperidone andziprasidone. In one embodiment of the present invention, the atypicalantipsychotic agent is aripiprazole.

Thus, as one specific aspect, the present invention provides acombination for the prevention, alleviation or treatment ofschizophrenia, comprising (a) a carbamate compound of Formula 1, or apharmaceutically acceptable salt, solvate or hydrate thereof; and (b)aripiprazole, or a pharmaceutically acceptable salt, solvate or hydratethereof.

In addition, the present invention provides a pharmaceutical compositionfor the prevention, alleviation or treatment of schizophrenia,comprising as active ingredients (a) a carbamate compound of Formula 1,or a pharmaceutically acceptable salt, solvate or hydrate thereof; and(b) aripiprazole, or a pharmaceutically acceptable salt, solvate orhydrate thereof; and further one or more of a pharmaceuticallyacceptable carrier.

In addition, the present invention provides a kit for the prevention,alleviation or treatment of schizophrenia, comprising (a) a firstcomposition comprising a carbamate compound of Formula 1, or apharmaceutically acceptable salt, solvate or hydrate thereof; and (b) asecond composition comprising aripiprazole, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, in a container.

Effect of the Invention

The combination and pharmaceutical composition of the present inventionprovide an improved effect of prevention, alleviation or treatment ofschizophrenia without increasing side effects. In one embodiment, thecombination and pharmaceutical composition of the present inventionexhibit a synergistic effect in the prevention, alleviation or treatmentof schizophrenia. In particular, the combination and pharmaceuticalcompositions of the present invention are effective in treating negativesymptoms of schizophrenia or ameliorating cognitive impairment.

In addition, by selecting the carbamate compounds of Formula 1 as a drughaving a mechanism of action different from that of the existingantipsychotic agents, and combining said carbamate compounds with theexisting atypical antipsychotic drug, aripiprazole, the combination andpharmaceutical composition of the present invention can reduce the sideeffects of the existing antipsychotic drugs while maintaining orelevating the drug efficacy even though the dose required for the drugefficacy is reduced.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of a test compound and aripiprazole of thesocial interaction animal behavior test related to negative symptoms ofschizophrenia in an animal model in which schizophrenia-like symptomswere induced by treatment with dizocilpine (MK-801). Description of eachsymbol in FIG. 1 is as follows:

Social interaction=the total amount of time spent in active socialinteraction

s=seconds

sc=mg/kg, subcutaneously

po=mg/kg, per os

−=Not treated

DETAILED DESCRIPTION

Hereinafter, the present invention will be described in detail.

The present invention provides a combination for the prevention,alleviation or treatment of schizophrenia, comprising (a) a carbamatecompound of the following Formula 1, or a pharmaceutically acceptablesalt, solvate or hydrate thereof; and (b) aripiprazole, or apharmaceutically acceptable salt, solvate or hydrate thereof:

wherein,

R₁ and R₂ are each independently selected from the group consisting ofhydrogen, halogen, C₁-C₈ alkyl, halo-C₁-C₈ alkyl, C₁-C₈ thioalkoxy andC₁-C₈ alkoxy; and

one of A₁ and A₂ is CH, and the other is N.

In addition, the present invention provides a pharmaceutical compositionfor the prevention, alleviation or treatment of schizophrenia,comprising as active ingredients (a) a carbamate compound of Formula 1,or a pharmaceutically acceptable salt, solvate or hydrate thereof; and(b) aripiprazole, or a pharmaceutically acceptable salt, solvate orhydrate thereof; and further one or more of a pharmaceuticallyacceptable carrier.

In addition, the present invention provides a kit for the prevention,alleviation or treatment of schizophrenia, comprising (a) a firstcomposition comprising a carbamate compound of Formula 1, or apharmaceutically acceptable salt, solvate or hydrate thereof; and (b) asecond composition comprising aripiprazole, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, in a container.

In addition, the present invention provides a method for preventing,alleviating or treating schizophrenia, comprising administering to asubject in need of such treatment a therapeutically effective amount of(a) a carbamate compound of Formula 1, or a pharmaceutically acceptablesalt, solvate or hydrate thereof; and of (b) aripiprazole, or apharmaceutically acceptable salt, solvate or hydrate thereof.

In addition, the present invention provides the use of a combinationcomprising (a) a carbamate compound of Formula 1, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof; and (b) aripiprazole, or apharmaceutically acceptable salt, solvate or hydrate thereof, for theprevention, alleviation or treatment of schizophrenia.

According to one embodiment of the present invention, in the abovecombination the components (a) and (b) may be administeredsimultaneously, separately or sequentially.

According to one embodiment of the present invention, in the above kit(a) the first composition and (b) the second composition may beadministered simultaneously, separately or sequentially.

According to one embodiment of the present invention, in the abovemethod of prevention, alleviation or treatment, the components (a) and(b) may be administered to the subject simultaneously, separately orsequentially.

According to one embodiment of the present invention, in the above usethe components (a) and (b) may be administered simultaneously,separately or sequentially.

In one embodiment of the present invention, in the above Formula 1, R₁and R₂ are each independently selected from the group consisting ofhydrogen, halogen and C₁-C₈ alkyl.

In one embodiment of the present invention, the halo C₁-C₈ alkyl isperfluoroalkyl.

According to another embodiment of the present invention, the carbamatecompound of the above Formula 1 is carbamic acid(R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of the followingFormula 2:

A person having ordinary skill in the art of synthesis of compoundscould have easily prepared the carbamate compounds of the above Formulas1 and 2 using known compounds or compounds which can be easily preparedtherefrom. In particular, methods for preparing the compounds of theabove Formula 1 are described in detail in PCT Publication Nos. WO2006/112685 A₁, WO 2010/150946 A₁ and WO 2011/046380 A₂, the disclosuresof which are incorporated herein by reference. The compounds of theabove Formula 1 can be chemically synthesized by any of the methodsdescribed in the above documents, but the methods are merely exemplaryones, and the order of the unit operation and the like may beselectively changed if necessary. Hence, the above methods are notintended to limit the scope of the invention.

Aripiprazole is a product marketed under the trade name Abilify®. Thechemical name is7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one,and the structure is as follows:

In one embodiment of the present invention, in addition to aripiprazole,an atypical antipsychotic agent selected from the group consisting ofasenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone,quetiapine, risperidone and ziprasidone may also be preferably used.

In the present invention, as the compounds of the above Formula 1 or 2and aripiprazole, their free form, or a pharmaceutically acceptablesalt, solvate or hydrate thereof, may be used.

According to one embodiment of the present invention, as the compoundsof the above Formula 1 or 2 and aripiprazole, their free form may beused.

For instance, examples of the pharmaceutically acceptable salts of thecompounds of the above Formula 1 or 2, or the pharmaceuticallyacceptable salts of aripiprazole, include independently, acetate,benzenesulfonate, benzoate, bitartrate, calcium acetate, camsylate,carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycoloyl arsanilate,hexylresorcinate, hydravamine, hydrobromide, hydrochloride,hydrogencarbonate, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate, methylnitrate,methylsulfate, mucate, napsylate, nitrate, pamoate (embonate),pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, subacetate, succinate or hemi-succinate, sulfate orhemi-sulfate, tannate, tartrate, oxalate or hemi-tartrate, teoclate,triethiodide, benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, ammonium,tetramethylammonium, calcium, lithium, magnesium, potassium, sodium andzinc.

In the combination or pharmaceutical composition according to oneembodiment of the present invention, a therapeutically effective amountor dose of the compounds of Formula 1 may include 12.5 to 500 mg, 12.5to 400 mg, 25 to 400 mg, 25 to 300 mg, 25 to 200 mg, 50 to 400 mg, 50 to300 mg, 50 to 200 mg, or 100 to 200 mg, based on the free form andonce-daily administration to humans.

In the combination or pharmaceutical composition according to oneembodiment of the present invention, a therapeutically effective amountor dose of aripiprazole may include 5 to 90 mg, preferably 5 to 60 mg,more preferably 5 to 30 mg, based on the free form and once-dailyadministration to humans.

In one embodiment of the present invention, the dose of the atypicalantipsychotic agent including aripiprazole may be lower than the doserequired for exhibiting a therapeutically effective amount whenadministered alone without the carbamate compounds of Formula 1. This isdue to the combination with the carbamate compounds of Formula 1, whichmakes it possible to maintain an effective pharmacological effect whilelowering the dose required for the pharmacological effect of theatypical antipsychotic agent.

According to one embodiment of the present invention, the combinationweight ratio of the component a) a carbamate compound of Formula 1, or apharmaceutically acceptable salt, solvate or hydrate thereof; to thecomponent b) aripiprazole, or a pharmaceutically acceptable salt,solvate or hydrate thereof is 1:1 to 40:1, 1:1 to 20:1, 2:1 to 20:1, or2:1 to 10:1.

The combination and pharmaceutical composition of the present inventioncan be prepared in various forms of oral or parenteral formulations, andmay be administered by, for example, intravenous injection,intramuscular injection, intracutaneous injection, subcutaneousinjection, intraduodenal injection, intraperitoneal injection orintrathecal injection, or they may also be administered by a transdermalroute. In addition, the composition can be administered by any devicecapable of transferring the active substance to a target cell. The routeof administration may vary depending upon the general condition and ageof the subject to be treated, the nature of the treatment condition andthe active ingredient selected.

A suitable dosage of the combination or pharmaceutical compositionaccording to one embodiment of the present invention may vary dependingon factors such as the formulation method, administration method, age,body weight and gender of patients, pathological condition, diet,administration time, administration route, excretion rate and reactionsensitivity, and doctors having ordinary skill can easily determine andprescribe dosages that are effective for the desired treatment orprophylaxis. The pharmaceutical composition according to one embodimentmay be administered in one or more doses, for example, one to four timesper day. The pharmaceutical composition according to one embodiment maycontain a) the compounds of Formula 1 in the amount of 12.5 to 500 mg,12.5 to 400 mg, 25 to 400 mg, 25 to 300 mg, 25 to 200 mg, 50 to 400 mg,50 to 300 mg, 50 to 200 mg, or 100 to 200 mg, based on the free form;and b) aripiprazole in the amount of 5 to 90 mg, preferably 5 to 60 mg,more preferably 5 to 30 mg, based on the free form.

The pharmaceutical composition according to one embodiment of thepresent invention may be formulated using a pharmaceutically acceptablecarrier and/or excipient according to a method that a person havingordinary skill in the art could easily carry out, thereby to be preparedin a unit dose form or to be contained in a multi-dose container. Theabove formulation may be a solution in oil or an aqueous medium, asuspension or an emulsion (emulsified solution), an extract, a powder,granules, a tablet, or a capsule, and may further include a dispersingor stabilizing agent. In addition, the pharmaceutical composition may beadministered in the form of suppositories, sprays, ointments, creams,gels, inhalants or skin patches. The pharmaceutical composition may alsobe prepared for mammalian administration, more preferably for humanadministration.

The pharmaceutical composition of the present invention furthercomprises one or more pharmaceutically acceptable carriers in additionto the active ingredients (a) and (b) as described above.

Pharmaceutically acceptable carriers may be solid or liquid, and may beone or more selected from fillers, antioxidants, buffers, bacteriostats,dispersants, adsorbents, surfactants, binders, preservatives,disintegrants, sweeteners, flavors, glidants, release-controllingagents, wetting agents, stabilizers, suspending agents, and lubricants.In addition, the pharmaceutically acceptable carriers may be selectedfrom saline, sterile water, Ringer's solution, buffered saline, dextrosesolution, maltodextrin solution, glycerol, ethanol and mixtures thereof.

In one embodiment, suitable fillers include, but are not limited to,sugar (e.g., dextrose, sucrose, maltose and lactose), starch (e.g., cornstarch), sugar alcohol (e.g., mannitol, sorbitol, maltitol, erythritoland xylitol), starch hydrolysate (e.g., dextrin and maltodextrin),cellulose or cellulose derivatives (e.g., microcrystalline cellulose) ormixtures thereof.

In one embodiment, suitable antioxidants include, but are not limitedto, tocopherol, ascorbic acid, gallate and the like.

In one embodiment, a suitable buffer may be citric acid monohydrate.

In one embodiment, suitable surfactants (emulsifiers) include, but arenot limited to, anionic, cationic or nonionic surfactants, such assodium laurate, sodium lauryl sulfate, sodium dodecanesulfonate, sodiumoleyl sulfate, benzalkonium chloride, alkyltrimethyl ammonium bromide,glyceryl monooleate, polyoxyethylene dried sorbitan fatty acid ester,polyvinyl alcohol and dried sorbitan S or mixtures thereof.

In one embodiment, suitable binders include, but are not limited to,povidone, copovidone, methylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxyethylcellulose, gelatin, gum, sucrose, starch or mixturesthereof.

In one embodiment, suitable preservatives include, but are not limitedto, benzoic acid, sodium benzoate, benzyl alcohol, butylatedhydroxyanisole, butylated hydroxytoluene, chlorbutol, gallate,hydroxybenzoate, EDTA or mixtures thereof.

In one embodiment, suitable disintegrants include, but are not limitedto, sodium starch glycolate, cross-linked polyvinylpyrrolidone,cross-linked carboxymethylcellulose, starch, microcrystalline celluloseor mixtures thereof.

In one embodiment, suitable sweeteners include, but are not limited to,sucralose, saccharin, sodium saccharin, potassium saccharin, calciumsaccharin, acesulfame potassium or sodium cyclamate, mannitol, fructose,sucrose, maltose or mixtures thereof.

In one embodiment, suitable glidants include, but are not limited to,colloidal silicon dioxide.

In one embodiment, suitable release-controlling agents(release-modifying excipients) include, but are not limited to,hydroxypropyl methylcellulose, polyethylene oxide, carbomer,pH-independent polymers such as alginic acid, pH-dependent polymers ormixtures thereof.

In one embodiment, suitable wetting agents include, but are not limitedto, hypromellose (HPMC), a polyoxyethylene derivative of sorbitanesters, such as polysorbate 20 and polysorbate 80, lecithin,polyoxyethylene- and polyoxypropylene ether, sodium deoxycholate ormixtures thereof.

In one embodiment, suitable suspending agents include, but are notlimited to, cellulose derivatives such as microcrystalline cellulose,methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, alginate, chitosan, dextran, gelatin,polyethylene glycol, polyoxyethylene- and polyoxypropylene ether ormixtures thereof.

In one embodiment, suitable lubricants include, but are not limited to,long chain fatty acids and salts thereof, such as magnesium stearate andstearic acid, talc, glyceride wax or mixtures thereof.

The pharmaceutical composition of the present invention may beformulated into an injectable formulation such as an aqueous solution, asuspension or an emulsion, or may be formulated into pills, capsules,granules or tablets. In powders, the carrier may be a fine solid thatcan be mixed with the active ingredient in the form of a mixture, and intablets, the active ingredient can be mixed with the carrier to havebinding properties that can be tabletted in an appropriate proportionand desired shape and size.

The pharmaceutical composition of the present invention may be preparedin capsule form.

For example, the pharmaceutical composition of the present invention maybe prepared in capsules that contain a) the compounds of Formula 1 inthe amount of 12.5 to 500 mg, 12.5 to 400 mg, 25 to 400 mg, 25 to 300mg, 25 to 200 mg, 50 to 400 mg, 50 to 300 mg, 50 to 200 mg, or 100 to200 mg, based on the free form; and b) aripiprazole in the amount of 5to 90 mg of, preferably 5 to 60 mg, more preferably 5 to 30 mg, based onthe free form; and gelatin and titanium dioxide as a capsule base. Theabove amount can be adjusted as needed.

The combinations and pharmaceutical compositions of the presentinvention have medicinal uses for the prevention, alleviation ortreatment of schizophrenia.

According to one embodiment of the present invention, the symptoms ofschizophrenia may be one or more selected from the group consisting ofpositive symptoms, negative symptoms, cognitive symptoms and residualsymptoms of schizophrenia.

According to one embodiment of the present invention, the schizophreniamay be one or more selected from the group consisting of paranoidschizophrenia, disorganized schizophrenia, catatonic schizophrenia,undifferentiated schizophrenia, residual schizophrenia,post-schizophrenic depression, simple schizophrenia, unspecifiedschizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to another medical condition,substance/medication-induced psychotic disorder, and psychotic disorderof unknown cause.

The antipsychotic activity of the carbamate compounds of Formula 1 andaripiprazole against schizophrenia can be tested through socialinteraction animal behavior tests used in drug development for thenegative symptoms of schizophrenia (Neill JC, Grayson B, Kiss B,Gyertyán I, Ferguson P, Adham N, Effects of cariprazine, a novelantipsychotic, on cognitive deficit and negative symptoms in a rodentmodel of schizophrenia symptomatology, Eur Neuropsychopharmacol. 2016Jan.;26(1):3-14). Since the effect of administration ofN-methyl-D-aspartate (NMDA) receptor inhibitor and symptoms due toschizophrenia are similar, animals administered withN-methyl-D-aspartate (NMDA) receptor inhibitor can be used as the modelof schizophrenia. Dizocilpine (MK-801) is an N-methyl-D-aspartate (NMDA)receptor inhibitor. In the dizocilpine-induced (MK-801-induced) socialinteraction animal behavior test, schizophrenia-like symptoms can beinduced by administration of dizocilpine (Rung JP, Carlsson A, RydénMarkinhuhta K, Carlsson ML, (+)-MK-801 induced social withdrawal inrats; a model for negative symptoms of schizophrenia. ProgNeuropsychopharmacol Biol Psychiatry. 2005 Jun.;29(5):827-32).Aripiprazole, known as an atypical antipsychotic drug, inhibitsschizophrenia-like symptoms in proportion to the dose of dizocilpine(Deiana S, Watanabe A, Yamasaki Y, Amada N, Kikuchi T, Stott C, RiedelG, MK-801-induced deficits in social recognition in rats: reversal byaripiprazole, but not olanzapine, risperidone, or cannabidiol. BehavPharmacol. 2015 Dec.;26(8 Spec No):748-65).

The dosage of the carbamate compounds of Formula 1 and aripiprazole forthe prevention, alleviation or treatment of the above diseases maytypically vary depending on the severity of the disease, the body weightand the metabolic status of the subject. A “therapeutically effectiveamount” for an individual patient refers to an amount of the activecompound sufficient to achieve the above pharmacological effect, i.e.,the therapeutic effect as described above.

As used herein, the terms “prevent,” “preventing” and “prevention” referto reducing or eliminating the likelihood of a disease.

As used herein, the terms “alleviate,” “alleviating” and “alleviation”refer to ameliorating a disease and/or its accompanying symptomsaltogether or in part.

As used herein, the terms “treat,” “treating” and “treatment” refer toeliminating a disease and/or its accompanying symptoms altogether or inpart.

As used herein, the term “subject” refers to an animal that is theobject of therapy, observation or experiment, preferably a mammal (suchas primates (e.g., a human), cattle, sheep, goats, horses, dogs, cats,rabbits, rats, mice, etc.), most preferably a human.

As used herein, the term “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical formulation that elicitsa biological or medical response in the system, animal or human,including alleviation of the symptoms of the disease or disorder to betreated, wherein said amount is sought by a researcher, veterinarian,doctor (physician) or other clinician.

As used herein, the term “blend or mixture or combination” or “combinedtherapy” means that two or more drugs are used together, but does notnecessarily mean a state in which two or more drugs are mixed. It meansthat two or more drugs may be present together in a single preparationin a mixed state, or may be used as separate preparations. In otherwords, the term “combination” includes a single preparation and also twoseparate preparations, so simultaneous, separate or sequentialadministration is possible.

As used herein, the term “composition” refers to a single preparation inwhich two or more drugs are present in a mixed state.

As used herein, the term “kit” typically means a finished product, andwhen two or more drugs are used, means a finished product containingthese drugs in the form of a combination. Two or more drugs may bepackaged in a single formulation in the finished product andadministered simultaneously, or may be packaged in two separateformulations in the finished product and administered simultaneously,separately or sequentially.

Hereinafter, the present invention will be explained in more detailthrough working examples. The objects, features and advantages of thepresent invention will be readily understood through the followingworking examples. The present invention is not limited to the workingexamples described herein, but may be embodied in other forms. Theworking examples described herein are provided to ensure that thedisclosed contents are thorough and complete, and that the technicalconcept of the present invention is sufficiently conveyed to a personskilled in the art to which the present invention pertains. Therefore,the present invention should not be limited by the following workingexamples.

Preparation Example: Synthesis of carbamic acid(R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester (thecompound of Formula 2, hereinafter referred to as “test compound”) wasprepared according to the method described in Preparation Example 50 ofPCT Publication No. WO 2010/150946.

Example: Effects in Social Interaction Animal Behavior Tests in AnimalModels with Schizophrenia-like Symptoms Induced by Dizocilpine Treatment

Experimental Animals

Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased,divided into 2 groups in an animal breeding room and acclimatized formore than 1 week on separate shelves. The experimental animals werehoused and maintained in accordance with the Laboratory Animal CareStandards of the Institutional Animal Care and Use Committee (IACUC)under conditions of light-and-darkness cycle of 12 hours, a temperatureof 22 to 25° C., a relative humidity of 40-60% and free access to foodand water. After stabilization for more than a week, the rats were usedin a social interaction animal behavior test in pairs of rats whoseweight difference did not exceed 20 g.

Social Interaction Animal Behavior Tests

Symptoms resulting from administration of N-methyl-D-aspartate (NMDA)receptor inhibitor and symptoms due to schizophrenia are similar. Thus,an animal model is used in which schizophrenia-like symptoms can beinduced by treatment of dizocilpine, an N-methyl-D-aspartate (NMDA)receptor inhibitor.

Dizocilpine (purchased from Sigma) was newly prepared by dissolving itin physiological saline used as a vehicle, and 4 hours before theexperiment, a 0.1 mg/kg dose was administered subcutaneously in a volumeof 1 ml per 1 kg of body weight of the rat.

Aripiprazole and the test compound were newly prepared by dissolvingthem in 30% polyethylene glycol 400 (Sigma) used as a vehicle. One hourbefore the experiment, a 0.003 mg/kg dose of aripiprazole and a 3 mg/kgdose of the test compound were administered orally in a volume of 1 mlper 1 kg of body weight of the rat.

The male rats were placed in the same observation box in pairs, allowing1:1 interaction, and then the total time of sniffing, grooming, licking,mounting and crawling under or over the other rat which can beconsidered as active social interactions was measured for 5 minutes, andsocial interaction was evaluated based on that.

Statistical Analysis of Experimental Results

All data are expressed as mean±SEM. Statistical analysis of the totaltime of active social interactions between groups was performed usingthe GraphPad Prism ver. 5.04 program, and analyzed by one-way ANOVA(one-way analysis of variance) and Dunnett's multiple comparison test.

The total time average of active social interactions in the negativecontrol group treated with dizocilpine only was observed to be53.86±2.90 seconds, and the total time average of active socialinteractions in the positive control vehicle group was observed to be69.63±3.13 seconds. The total time average of active social interactionswas observed to be 57.52±3.04 seconds in the aripiprazole 0.003 mg/kgadministration group, 56.78±2.19 seconds in the test compound 3 mg/kgadministration group, and 63.76±1.87 seconds in the group administeredwith aripiprazole 0.003 mg/kg and the test compound 3 mg/kg.

TABLE 1 Effects of aripiprazole and the test compound on the socialinteraction animal behavior test treated with dizocilpine DoseDizocilpine Aripiprazole Test Number Social Drugs (mg/kg, (mg/kg,compound of interaction ¹⁾ administered sc ²⁾) po ³⁾) (mg/kg, po)animals (Mean ± SEM) Vehicle — ⁴⁾ — — 20 pairs 69.63 ± 3.13 Dizocilpine0.1 — — 20 pairs 53.86 ± 2.90 Aripiprazole 0.1 0.003 — 20 pairs 57.52 ±3.04 Test 0.1 — 3 20 pairs 56.78 ± 2.19 compound Aripiprazole 0.1 0.0033 20 pairs 63.76 ± 1.87 and test compound ¹⁾ Social interaction = Totaltime of active social interactions of sniffing, grooming, licking,mounting and crawling (unit: second) ²⁾ sc = mg/kg, subcutaneously ³⁾ po= mg/kg, per os ⁴⁾ — = Not treated

Table 2 shows recovery rate (%) which represents the total time ofactive social interactions in the test compound and/or aripiprazoletreated group and the positive control vehicle group, compared to thatin the negative control group treated with dizocilpine only. Therecovery rate was calculated as follows.

Recovery rate (%)=(Time of active social interactions in test group−Timeof active social interactions in negative control group)/(Time of activesocial interactions in positive control group−Time of active socialinteractions in negative control group)×100

TABLE 2 Summary of recovery rate compared to negative control group insocial interaction animal behavior test treated with dizocilpine andstatistical significance Recovery rate Statistical Statistical comparedsignificance significance Number to compared to compared to Drugs ofnegative negative control positive control administered animals control(P < 0.05?) (P < 0.05?) Vehicle 20 pairs 100.0% Significant Dizocilpine20 pairs  0.0% Significant Aripiprazole 20 pairs  23.2% Not significantSignificant Test 20 pairs  18.5% Not significant Significant compound  Aripiprazole 20 pairs  62.8% Significant Not significant and testcompound

The aripiprazole administration group and the test compoundadministration group showed recovery rates of 23.2% and 18.5%,respectively, compared to the negative control group, and showed nostatistically significant difference from the negative control grouptreated with dizocilpine only, and showed a statistically significantdifference from the positive control group. While the respectiveadministration of aripiprazole 0.003 mg/kg or the test compound 3 mg/kgdid not show a significant recovery effect compared to the negativecontrol group, the group administered with these doses together showed arecovery rate of 62.8% compared to the negative control group, showing astatistically significant difference from the negative control group andno statistically significant difference from the positive control group(FIG. 1 ).

From the above, it was confirmed that a combination of aripiprazole andthe test compound shows a synergistic increase in the effect on socialinteraction. This indicates that these two drugs are effective intreating schizophrenia, especially the negative symptoms ofschizophrenia.

1. A combination for the prevention, alleviation or treatment ofschizophrenia, comprising (a) a carbamate compound of the followingFormula 1, or a pharmaceutically acceptable salt, solvate or hydratethereof; and (b) aripiprazole, or a pharmaceutically acceptable salt,solvate or hydrate thereof:

wherein, R₁ and R₂ are each independently selected from the groupconsisting of hydrogen, halogen, C₁-C₈ alkyl, halo-C₁-C₈ alkyl, C₁-C₈thioalkoxy and C₁-C₈ alkoxy; and one of A₁ and A₂ is CH, and the otheris N. 2-22. (canceled)
 23. A composition comprising (a) a carbamatecompound of the following Formula 1, or a pharmaceutically acceptablesalt, solvate or hydrate thereof; (b) an antipsycotic agent selectedfrom the group consisting of haloperidol, chlorpromazine, aripiprazole,asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone,quetiapine, risperidone, ziprasidone, and a pharmaceutically acceptablesalt, solvate or hydrate thereof; and (c) a pharmaceutically acceptablecarrier:

wherein, R₁ and R₂ are each independently selected from the groupconsisting of hydrogen, halogen, C₁-C₈ alkyl, halo-C₁-C₈ alkyl, C₁-C₈thioalkoxy and C₁-C₈ alkoxy; and one of A₁ and A₂ is CH, and the otheris N.
 24. The composition according to claim 23, wherein theantipsycotic agent is selected from the group consisting of haloperidol,chlorpromazine, and a pharmaceutically acceptable salt, solvate orhydrate thereof.
 25. The composition according to claim 23, wherein theantipsycotic agent is selected from the group consisting ofaripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone,paliperidone, quetiapine, risperidone, ziprasidone, and apharmaceutically acceptable salt, solvate or hydrate thereof.
 26. Thecomposition according to claim 23, wherein R₁ and R₂ are eachindependently selected from the group consisting of hydrogen, halogenand C₁-C₈ alkyl.
 27. The composition according to claim 23, wherein thecarbamate compound of Formula 1 is carbamic acid(R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of the followingFormula 2:


28. The composition according to claim 23, which comprises the compoundof Formula 1 in an amount of 12.5 mg to 500 mg based on the free form.29. The composition according to claim 23, wherein the pharmaceuticallyacceptable carrier is selected from fillers, antioxidants, buffers,bacteriostats, dispersants, adsorbents, surfactants, binders,preservatives, disintegrants, sweeteners, flavors, glidants,release-controlling agents, wetting agents, stabilizers, suspendingagents, and lubricants.
 30. The composition according to claim 23, whichthe pharmaceutically acceptable carrier is selected from saline, sterilewater, Ringer's solution, buffered saline, dextrose solution,maltodextrin solution, glycerol, ethanol and mixtures thereof.
 31. Thecomposition according to claim 29, wherein the fillers are selected fromgroup consisting of dextrose, sucrose, maltose, lactose, corn starch,mannitol, sorbitol, maltitol, erythritol, xylitol, dextrin,maltodextrin, microcrystalline cellulose, and mixtures thereof.
 32. Thecomposition according to claim 29, wherein the antioxidants are selectedfrom group consisting of tocopherol, ascorbic acid, and gallate.
 33. Thecomposition according to claim 29, wherein the buffer is citric acidmonohydrate.
 34. The composition according to claim 29, wherein thesurfactants are selected from group consisting of sodium laurate, sodiumlauryl sulfate, sodium dodecanesulfonate, sodium oleyl sulfate,benzalkonium chloride, alkyltrimethyl ammonium bromide, glycerylmonooleate, polyoxyethylene dried sorbitan fatty acid ester, polyvinylalcohol, dried sorbitan S and mixtures thereof.
 35. The compositionaccording to claim 29, wherein the binders are selected from groupconsisting of povidone, copovidone, methylcellulose,hydroxymethylcellulose, hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gum, sucrose,starch or mixtures thereof.
 36. The composition according to claim 29,wherein the preservatives are selected from group consisting of benzoicacid, sodium benzoate, benzyl alcohol, butylated hydroxyanisole,butylated hydroxytoluene, chlorbutol, gallate, hydroxybenzoate, EDTA,and mixtures thereof.
 37. The composition according to claim 29, whereinthe disintegrants are selected from group consisting of sodium starchglycolate, cross-linked polyvinylpyrrolidone, cross-linkedcarboxymethylcellulose, starch, microcrystalline cellulose, and mixturesthereof.
 38. The composition according to claim 29, wherein the glidantsare colloidal silicon dioxide.
 39. The composition according to claim29, wherein the release-controlling agents are selected from groupconsisting of hydroxypropyl methylcellulose, polyethylene oxide,carbomer, pH-independent polymers such as alginic acid, pH-dependentpolymers, and mixtures thereof.
 40. The composition according to claim29, wherein the wetting agents are selected from group consisting ofhypromellose, polysorbate 20, polysorbate 80, lecithin, polyoxyethylene-and polyoxypropylene ether, sodium deoxycholate, and mixtures thereof.41. The composition according to claim 29, wherein the suspending agentsare selected from group consisting of microcrystalline cellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, alginate, chitosan, dextran, gelatin,polyethylene glycol, polyoxyethylene- and polyoxypropylene ether, andmixtures thereof.
 42. The composition according to claim 29, wherein thelubricants are selected from group consisting of magnesium stearate,stearic acid, talc, glyceride wax, and mixtures thereof.
 43. A methodfor preventing, alleviating or treating schizophrenia, comprising:administering to a subject in need thereof the composition of claim 23.